Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 48, Pages 37445-37457Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.125542
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Funding
- National Institutes of Health [5R01GM085081, RO1NS050199, R01NS055247, T32 AG000266-10]
- Parkinson's Disease Foundation
- High Q Foundation
- Arnold and Mabel Beckman Foundation
- Cure Huntington Disease Initiative, Inc.
- Hereditary Disease Foundation
- Burroughs Wellcome Fund
- Buck Trust
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Cellular responses to drug treatment show tremendous variations. Elucidating mechanisms underlying these variations is critical for predicting therapeutic responses and developing personalized therapeutics. Using a small molecule screening approach, we discovered how a disease causing allele leads to opposing cell fates upon pharmacological perturbation. Diverse microtubule-depolymerizing agents protected mutant huntingtin-expressing cells from cell death, while being toxic to cells lacking mutant huntingtin or those expressing wild-type huntingtin. Additional neuronal cell lines and primary neurons from Huntington disease mice also showed altered survival upon microtubule depolymerization. Transcription profiling revealed that microtubule depolymerization induced the auto-crine growth factor connective tissue growth factor and activated ERK survival signaling. The genotype-selective rescue was dependent upon increased RhoA protein levels in mutant huntingtin-expressing cells, because inhibition of RhoA, its downstream effector, Rho-associated kinase ( ROCK), or a microtubule-associated RhoA activator, guanine nucleotide exchange factor-H1 (GEF-H1), all attenuated the rescue. Conversely, RhoA overexpression in cells lacking mutant huntingtin conferred resistance to microtubule-depolymerizer toxicity. This study elucidates a novel pathway linking microtubule stability to cell survival and provides insight into how genetic context can dramatically alter cellular responses to pharmacological interventions.
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